Developing Personalized Medicine for Lung Cancer. The University of Texas SPORE in Lung Cancer represents a unique collaboration between the University of Texas Southwestern Medical Center (UTSW) and the University of Texas MD Anderson Cancer Center (MDACC) both of which have outstanding Strengths in lung cancer translational research. The overarching goal of the SPORE is to develop new experimental paradigms leading to personalized medicine approaches for lung cancer based on a molecular understanding of lung cancers in individual patients, and using this information to select the therapy (personalize) of each NSCLC patient's treatment. The SPORE builds on a 16 year productive history and incorporates recent advances made by SPORE investigators and others in lung cancer genomics, as well as important new advances in identifying and understanding lung cancer acquired vulnerabilities (synthetic lethalities). Together this will provide a more complete mechanistic understanding of the molecular findings so they can be applied to patients. These advances include novel approaches to functionally classify lung cancer by determining precisely the acquired vulnerabilities of each tumor, studying new molecular classifications of NSCLC related mRNA expression and DNA mutational clades and their functional characteristics, developing tools for CLIA certifiable molecular classification tests, preclinical model systems for testing the value of these new classification schemes, and a large legacy of molecular and clinical annotated datasets of lung cancers for retrospective analyses. The SPORE is composed of 4 projects: #1. Personalized medicine for NSCLC based on molecular portraits/clades; #2. Epidemiologic study of the role miR polymorphisms for predicting risk of lung cancer development and recurrence; #3. Therapeutic targeting of PI3K and MEK in mutant KRAS driven lung cancer for radiosensitization and blocking metastases; and #4. Therapeutic targeting of telomerase dependence on maintaining telomeres in lung cancer stem cells. In addition there are three cores: A. Administrative (including patient advocates), B. Molecular pathology, and C. Biostatistics-bioinformatics. The SPORE has some of the leading lung cancer translational investigators in the world in addition to a multidisciplinry group of clinical and laboratory scientists as well as a cadre of experienced patient advocates. The projects planned in this SPORE application will provide a new functional classification of lung cancer therapeutics, and the opportunity to change the face of NSCLC therapy.